The present invention relates to glycoconjugates of camptothecin derivatives in which at least one carbohydrate component is linked via suitable spacers with the 20-hydroxyl group of a camptothecin derivative. The invention furthermore relates to processes for preparing the compounds according to the invention and to their use as medicaments, in particular in connection with cancer.
20(S)-Camptothecin is a pentacyclic alkaloid which was isolated in 1966 by Wall et al. (J.Am.Chem.Soc. 88, 3888 (1966)). It has a high antitumour activity potential in numerous in vitro and in vivo tests. Unfortunately, however, the promising potential failed to be realized in the clinic because of toxicity and solubility problems.
By opening the E ring lactone and formation of the sodium salt, a water-soluble compound was obtained which is in a pH-dependent equilibrium with the ring-closed form. Here too, clinical studies have been unsuccessful until now. 
Approximately 20 years later, it was found that the biological activity is to be attributed to an enzyme inhibition of the topoisomerase I. Since then, the research activities have been increased again in order to find camptothecin derivatives which are more compatible and active in vivo.
To improve the water-solubility, salts of A ring- and B ring-modified camptothecin derivatives and of 20-O-acyl derivatives having ionizable groups have been described (Vishnuvajjala et al. U.S. Pat. No. 4,943,579). The latter prodrug concept was later also applied to modified camptothecin derivatives (Wani et al. WO 9602546). In vivo, however, the 2-O-acyl prodrugs described have a very short half-life and are very rapidly cleaved to give the parent structure.
Surprisingly, we have now found that the linkage of carbohydrate derivatives for example via peptide spacers on the 20-hydroxyl group of A- and/or B-ring-modified camptothecin derivatives leads to a class of compounds having highly interesting properties:
By means of the ester-like linkage of the carrier radicals to the 20-hydroxyl group, the lactone ring in the camptothecin derivatives, which is important for the action, is stabilized.
The conjugates obtained in this manner have high in vitro activity against tumour cell lines and tumour xenografts.
Compared with the underlying toxophores, they have markedly higher tolerability and tumour selectivity and improved solubility, in particular in aqueous media.
In vivo, they exhibit excellent therapeutic activity over several dose stages.
In extracellular medium and in blood, they are considerably more stable than the above-described 20-O-acyl prodrugs of camptothecin.
The invention relates to compounds of the general formula (I)
Axe2x80x94Cpxe2x80x94Bxe2x80x83xe2x80x83(I)
in which
Cp represents a group of the formulae 
in which
R1, R2, R3 and R4 independently of one another may represent hydrogen, alkyl having up to 3 carbon atoms, halogen, amino, hydroxyl or nitro or
R2 and R3 together represent a group of the formula 
m may have the values 1 or 2 and
R5 represents xe2x80x94CH2xe2x80x94Oxe2x80x94*, xe2x80x94CH2xe2x80x94NH*, 
or represents 
in which R6 represents arylmethyl or hetarylmethyl, 
in which
R7 and R8 are as defined for R2 and R3 and may be identical or different to these, 
in which
R9 represents hydrogen or xe2x80x94CH2xe2x80x94N(CH3)2 and
R10 represents hydrogen or ethyl,
or 
in which
R11 and R12 are as defined for R2 and R3 and may be identical or different to these,
or 
in which
R13 and R14 are as defined for R2 and R3 and may be identical or different to these,
where Cp is attached to A on the positions labelled # and attached to B on the positions labelled *,
A represents a radical of the formula 
where 1xe2x89xa6(n+o+p)xe2x89xa63,
B represents hydrogen or a radical of the formula 
where 0xe2x89xa6(q+r+s)xe2x89xa63, in which
M1 and M2 independently of one another each represent a bridge grouping whose main chain includes up to 21 atoms in linear order,
L1, L2, L3, L4, L5 and L6 independently of one another each represent linker groupings customaily used in glycoconjugate chemistry, (see review article Lee Y. C. and Lee R. in Lectins and Cancer 1991, 53-69, ed. by Gabius H. J. and Gabius S., Springer-Verlag),
Sp1, Sp2, Sp3, Sp4, Sp5 and Sp6 independently of one another each represent arylene having up to 10 carbon atoms or represent alkylene having up to 8 carbon atoms which are in each case optionally substituted, and K1, K2, K3, K4, K5 and K6 independently of one another each represent a radical of the formula (II) 
in which
C represents methyl, hydroxymethyl, alkoxymethyl having up to 6 carbon atoms, acyloxymethyl having up to 6 carbon atoms or a radical of the formula xe2x80x94CH2xe2x80x94D in which
D represents a radical of the formula (II),
R15, R16 and R17 independently of one another each represent hydrogen, hydroxyl, optionally hydroxyl-substituted alkoxy having up to 6 carbon atoms, amino which is optionally substituted by alkyl or acyl having up to 6 carbon atoms, halogen, sulphate or a group of the formula 
in which
R18 and R19 independently of one another each represent hydroxyl or alkoxy having up to 6 carbon atoms or represent amino which is optionally substituted by alkyl having up to 6 carbon atoms, and
u and v independently of one another may each have the values 0, 1, 2, 3 or 4;
or
R15, R16 and R17 independently of one another each represent a radical of the formula (II)
or
two of the radicals R15, R16, R17 together represent an epoxy group,
or compounds of the formula: 
in which
R1, R2, R3, R4, and A are as defined above;
R5 represents H, xe2x80x94CH2CH3, 
or represents xe2x80x94CH2xe2x80x94N(CH2CH3)R6,
in which R6 represents arylmethyl or heterylmethyl,
and their isomers, isomer mixtures and salts.
Unless stated otherwise in the context of the invention, the term xe2x80x9calkyl groupsxe2x80x9d includes straight-chain, branched, cyclic and cycloalkyl-radical-containing alkyl radicals. Correspondingly, this definition also applies to all the other radicals containing alkyl groups, such as, for example, alkoxy, acyl, etc.
The terms arylmethyl and hetarylmethyl given in the definition of R6 may represent, for example, phenylmethyl or pyridylmethyl.
Preference is given to compounds of the general formula (I) in which K1, K2, K3, K4, K5 and K6 independently of one another may each represent a radical of the formula (II) where
C represents methyl, hydroxymethyl, methoxymethyl or acetoxymethyl,
R15 represents hydrogen, hydroxyl, methoxy or a group of the formula 
in which
u and v independently of one another may each have the values 1 or 2 and
R18 and R19 independently of one another each represent hydroxyl or alkoxy having up to 4 carbon atoms,
or
R15 represents a radical of the formula (II),
R16 represents hydrogen, hydroxyl, halogen, alkoxy having up to 4 carbon atoms, sulphate or a group of the formula 
in which
u and v independently of one another may each have the values 1 or 2 and
R18 and R19 independently of one another each represent hydroxyl or alkoxy having up to 4 carbon atoms or represent amino which is optionally substituted by alkyl having up to 4 carbon atoms,
R17 represents hydroxyl, alkoxy having up to 4 carbon atoms which is optionally substituted by hydroxyl, amino which is optionally substituted by alkyl or acyl having up to 4 carbon atoms, or a group of the formula 
in which
u and v independently of one another may each have the values 1 or 2 and
R18 and R19 independently of one another each represent hydroxyl or alkoxy having up to 4 carbon atoms,
or in which
R15 and R16 together represent an epoxy group,
and their isomers, isomer mixtures and salts.
Very particularly preferably, K1, K2, K3, K4, K5 and/or K6 represent a radical of the formula (II), where
C represents methyl, hydroxymethyl, methoxymethyl or acetoxymethyl,
R15 and R17 each represent a hydroxyl group and
R16 represents hydrogen, hydroxyl, halogen, alkoxy having up to 4 carbon atoms, sulphate or a group of the formula 
in which
u and v independently of one another may each have the values 1 or 2 and
R18 and R19 independently of one another each represent hydroxyl or alkoxy having up to 4 carbon atoms or represent amino which is optionally substituted by alkyl having up to 4 carbon atoms.
According to a particularly preferred embodiment, the carbohydrate building blocks K1, K2, K3, K4, K5 and/or K6 include in each case at most two monosaccharide building blocks.
Preference is furthermore given to compounds of the general formula (I) in which Sp1, Sp2, Sp3, Sp4, Sp5 and/or Sp6 independently of one another may each represent arylene having up to 10 carbon atoms which is attached to in each case one group K1, K2, K3, K4, K5 or K6 and L1, L2, L3, L4, L5 or L6 and which is optionally also mono- or polysubstituted by hydroxyl, carboxyl, carboxyalkyl having up to 4 carbon atoms, nitro, cyano, halogen, alkyl having up to 4 carbon atoms, halogenoalkyl having up to 4 carbon atoms or by alkoxy having up to 4 carbon atoms, and their isomers, isomer mixtures and salts.
Not taking K1, K2, K3, K4, K5 or K6 and L1, L2, L3, L4, L5 or L6 into account, Sp1, Sp2, Sp3, Sp4, Sp5 and/or Sp6 are particularly preferably unsubstituted or optionally substituted by halogen, nitro, alkyl having up to 6 carbon atoms, alkoxy having up to 2 carbon atoms, xe2x80x94OCF3 and/or CF3.
Very particularly preferably, Sp1, Sp2, Sp3, Sp4, Sp5 and/or Sp6 carry no other substituents apart from a group K1, K2, K3, K4, K5 or K6 and a group L1, L2, L3, L4, L5 or L6 each, which are attached para to one another.
Preference is furthermore given to compounds of the general formula (I) in which
L1, L2, L3, L4, L5 and L6 independently of one another each represent 
R20 represents chlorine or represents hydroxyalkylamino having up to 6 carbon atoms.
Particularly preferably, L1, L2, L3, L4, L5 and L6 each represent 
Preference is furthermore given to compounds of the general formula (I) in which M1 and M2 independently of one another may each represent a peptide which is attached to L1, L2, L3, L4, L5 and/or L6 via an amino function, is attached to Cp via an acyl function and whose amino acid building blocks may optionally carry protective groups. Particular preference is given to mono-, di- and tripeptides, in particular to mono- and dipeptides.
The amino acid building blocks are preferably selected from the group consisting of glycyl, alanyl, valyl, leucyl, lysyl, seryl, glutamyl, threonyl, asparagyl, isoleucyl, diaminopropionyl, diaminobutyryl, arginyl, histidyl and/or ornithyl.
Particular preference is given to the amino acid building blocks glycyl, alanyl, valyl, leucyl, lysyl, seryl, asparagyl, histidyl and/or glutamyl.
The compounds according to the invention may be present in stereoisomeric forms, for example as enantiomers or diastereomers, or as mixtures thereof, for example as a racemate. The invention relates both to the pure stereoisomers and to their mixtures.
If required, mixtures of stereoisomers can be separated into the stereoisomerically uniform components in a manner known per se, for example by chromatography or by crystallization processes.
The stereochemistry at the anomeric centre of the carbohydrate building blocks K1, K2, K3, K4, K5 and/or K6 may be xcex1 or xcex2. Furthermore, they may be present in the D or the L form. The stereochemistry at the other centres may result in the gluco, manno, galacto, gulo, rhamno or fuco configuration.
The amino acid building blocks may in each case be present in the D or in the L form.
The camptothecin building block Cp can be present in the 20-(R) or in the 20-(S) configuration or as a mixture of these two stereoisomeric forms. Preference is given to the 20-(S) configuration.
Furthermore, owing to restricted rotation, the compounds according to the invention may occur in the form of rotational isomers or as their mixtures. The invention relates both to the pure rotational isomers and to their mixtures.
Mixtures of rotational isomers can optionally, if required, be separated into the uniform components using known methods, for example by chromatography (for example HPLC) or by crystallization processes. This can be done at the stage of the final compound and, if appropriate, also at an intermediate stage. If appropriate, the rotamerically pure end products can be prepared from rotamerically pure intermediates by conducting the synthesis in an appropriate manner.
Preferred examples of the camptothecin building block are: 
Among these examples, particular preference is given to [A3], [A7], [A8], [A9], [A10], [A11], [A14], [B1], [B2], [C2] and [D1].
By combining the preferred or particularly preferred meanings given for the individual radicals, very particularly preferred compounds of the general formula (I) result correspondingly.
The compounds according to the invention may also be present in the form of their salts. In general, salts with organic or inorganic bases or acids and also inner salts may be mentioned here.
The acids which can be adducted preferably include hydrohalic acids, such as, for example, hydrochloric acid and hydrobrornic acid, in particular hydrochloric acid, furthermore phosphoric acid, nitric acid, sulphuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as, for example, acetic acid, trifluoroacetic acid, maleic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid and also sulphonic acids, such as, for example, p-toluenesulphonic acid, 1,5-naphthalenedisulphonic acid or camphorsulphonic acid.
Physiologically acceptable salts may also be the metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particular preference is given, for example, to sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or phenethylamine.
The glycoconjugates according to the invention can be prepared, for example, by linkage of modified camptothecin derivatives with activated carboxyl components, which for their part can be moieties of protected amino acids, peptides or carbohydrate-modified peptides.
The invention thus furthermore relates to a process for preparing compounds of the general formula (I), characterized in that compounds of the general formula (III)
HBxe2x80x94Cpxe2x80x94HAxe2x80x83xe2x80x83(III)
in which Cp is as defined above and the hydrogen atoms HA and HB are located on the positions labelled # and *, respectively, are reacted, if appropriate after replacing HB by a protective group, with an activated carboxyl component M1a which corresponds to the radical M1 defined above and optionally carries protective groups, in a suitable solvent, if appropriate in the presence of a base, by customary methods, one, more than one or all protective groups of M1 are, if appropriate, selectively removed by known methods and the product is reacted with compounds of the general formula (IV)
K1xe2x80x94Sp1xe2x80x94L1axe2x80x83xe2x80x83(IV)
in which K1 and Sp1 are each as defined above and L1a represents a reactive precursor of the group L1, where the protective groups are, if appropriate, selectively removed and various groups K2xe2x80x94Sp2xe2x80x94L2xe2x80x94 and K3xe2x80x94Sp3xe2x80x94L3xe2x80x94 can be introduced stepwise
in a comparable manner, and that, if a carbohydrate component is to be attached to the position labelled *, the protective group which replaces HB is, if appropriate, selectively removed by known methods and the radical M2 and, as desired, radicals of the formulae K4xe2x80x94Sp4xe2x80x94L4xe2x80x94, K5xe2x80x94Sp5xe2x80x94L5xe2x80x94 and K6xe2x80x94Sp6xe2x80x94L6xe2x80x94 are introduced in the manner described above
or that, if M1 and/or M2 are a peptide, a first amino acid radical is introduced in a comparable manner by customary methods in the form of a corresponding carboxyl component which optionally carries protective groups, protective groups are, if appropriate, removed, amino acid radicals which optionally carry protective groups are attached, protective groups are, if appropriate, removed again, the above-mentioned mentioned radicals of the formulae K1xe2x80x94Sp1xe2x80x94, L1xe2x80x94, K2xe2x80x94Sp2xe2x80x94L2xe2x80x94, K3xe2x80x94Sp3xe2x80x94L3xe2x80x94, K4xe2x80x94Sp4xe2x80x94L4xe2x80x94, K5xe2x80x94Sp5xe2x80x94L5xe2x80x94 and/or K6xe2x80x94Sp6xe2x80x94L6xe2x80x94 are introduced and, if required, protective groups are removed.
The reactions can be carried out under various pressure and temperature conditions, for example 0.5 to 2 bar, and xe2x88x9230 to +100xc2x0 C., in suitable solvents such as dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, chloroform, lower alcohols, acetonitrile, dioxane, water or in mixtures of the solvents mentioned. In general, reactions in DMF or THF/dichloromethane at room temperature and normal pressure are preferred.
For the activation of the carboxyl groups, possible coupling reagents are those known in peptide chemistry such as described, for example, in Jakubke/Jeschkeit: Aminosxc3xa4uren, Peptide, Proteine [Amino Acids, Peptides, Proteins]; Verlag Chemie 1982 or Tetrahedr. Lett. 34, 6705 (1993). Acyl chlorides, N-carboxylic anhydrides or mixed anhydrides, for example, are preferred.
Furthermore suitable for the activation of the carboxyl groups is the formation of adducts with carbodiimides, e.g. N,Nxe2x80x2-diethyl-, N,Nxe2x80x2-diisopropyl-, N,Nxe2x80x2-dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-Nxe2x80x2-ethyl-carbodiimide hydrochloride, N-cyclohexyl-Nxe2x80x2-(2-morpholinoethyl)-carbodiimide metho-p-toluenesulphonate, or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate, 1-hydroxybenzotriazole esters or hydroxysuccinimide esters. Furthermore, the amino acid components can also be employed in the form of a Leuchs"" anhydride.
Bases employed can be, for example, triethylamine, ethyl-diisopropylamine, pyridine, N,N-dimethylaminopyridine or others.
Protective groups employed for any other reactive functions in the camptothecin moiety or for third functions of the amino acids can be the protective groups known in peptide chemistry, for example of the urethane, alkyl, acyl, ester or amide type.
Amino protective groups in the context of the invention are the customary amino protective groups used in peptide chemistry.
These preferably include: benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyl-oxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), allyloxycarbonyl, vinyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, benzyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4-nitrophenyl or 2-nitrophenylsulphenyl. The Fmoc group and the Boc group are particularly preferred.
Preferred carboxyl protective groups are linear or branched C1-to C4-alkyl esters.
The camptothecin derivatives linked with a bridge grouping M1 and/or M2 can be modified with carbohydrate radicals using various methods and linker groups. Preference is given, for example, to converting p-amino-phenyl glycosides into isothiocyanates and linkage, for example, with amino groups. Furthermore, it is also easily possible to couple carboxyalkyl or aminoalkyl glycosides with amino or carboxyl groups.
The removal of protective groups in appropriate reaction steps can be carried out, for example, by the action of acid or base, hydrogenolytically or reductively in another manner.
Biological Testing
1. Growth Inhibition Test for the Determination of the Cytotoxic Properties
The human large intestine cell lines SW 480 and HT 29 (ATCC No. CCL 228 and HBT 38) and the mouse melanoma cell line B16F10 were grown in Roux dishes in RPMI 1640 medium with addition of 10% FCS. They were then trypsinized and taken up in RPMI plus 10% FCS to a cell count of 50,000 cells/ml. 100 xcexcl of cell suspension/well were added to a 96 microwell plate and incubated for 1 day at 37xc2x0 C. in a CO2 incubator. A further 100 xcexcl of RPMI Medium and 1 xcexcl of DMSO containing the test substances were then added. The growth was checked after day 3 and day 6. To this end, 40 xcexcl of MTT solution (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoline bromide) having a starting concentration of 5 mg/ml of H2O were added to each microwell. Incubation was carried out for 5 hours in a CO2 incubator at 37xc2x0 C. The medium was then aspirated and 100 xcexcl of i-propanol/well were added. After shaking for 30 min with 100 xcexcl of H2O, the extinction was measured at 540 nm using a Titertek Multiscan MCC/340 (Flow).
The cytotoxic action is indicated in Table 1 as the IC50 value in each case for the SW 480 and HT 29 and B16F10 cell lines:
2. Haematopoietic Activity of Glycoconjugates in Comparison with the Underlying Active Compound
Materials and Methods
Bone marrow cells were washed out of mice femurs. 105 cells were incubated at 37xc2x0 C. and 7% CO2 in McCoy 5A medium (0.3% agar) together with recombinant murine GM-CSF (Genzyme; stem cell colony formation) and the substances (10xe2x88x924 to 100 xcexcg/ml). 7 days later, the colonies ( less than 50 cells) and clusters (17-50 cells) were counted.
Results
As shown in Tab. 2, the glycoconjugates investigated show a drastically reduced inhibition of the bone marrow stem cell proliferation compared with the underlying active compound.
3. In vivo Inhibition of Tumour Growth in the Nude Mouse Model
Material
For all in vivo experiments for investigation of the inhibition of tumour growth athymic nude mice (NMRI nu/nu strain) were used. The selected large-cell lung carcinoma LXFL 529 was grown by serial passage in nude mice. The human origin of the tumour was confirmed by isoenzymatic and immunohistochemical methods.
Experimental Set-up
The tumour was implanted subcutaneously into both flanks of 6 to 8 week old nu/nu nude mice. The treatment was started, depending on the doubling time, as soon as the tumours had reached a diameter of 5-7 mm. The mice were assigned to the treatment group and the control group (5 mice per group with 8-10 assessable tumours) by randomization. The individual tumours of the control group all grew progessively.
The size of the tumours was measured in two dimensions by means of a slide gauge. The tumour volume, which correlated well with the cell count, was then used for all evaluations. The volume was calculated according to the formula xe2x80x9clengthxc3x97breadthxc3x97breadth/2xe2x80x9d ([axc3x97b2]/2, a and b represent two diameters at right angles).
The values of the relative tumour volume (RTV) were calculated for each individual tumour by dividing the tumour size on day X with the tumour size on day 0 (at the time of randomization). The mean values of the RTV were then used for the further evaluation.
The inhibition of the increase of the tumour volume (tumour volume of the test group/control group, T/C, in per cent) was the final measured value.
Treatment
The administration of the compounds was carried out intraperitoneally (i.p.) on day 1, 2 and 3 after randomization.
Results
Using the compound from Example 1.1, the therapeutic efficacy of the glycoconjugates according to the invention is compared with the large-cell human lung tumour xenograft LXFL 529. In the case of the maximum tolerable dose (MTD) and at xc2xd MTD, the therapy leads to marked tumour remission.
Both in vitro and in vivo, the compounds according to the invention have a surprisingly strong antitumour activity against various tumours, in particular those of the lungs and the large intestine, in combination with a high selectivity compared to non-malignant cells.
They are therefore suitable for treating cancer, in particular cancer of the lungs and the large intestine.
The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for the production of these preparations.
The active compound(s) can optionally be present in one or more of the excipients indicated above and also in microencapsulated form.
The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical preparations in a concentration of from approximately 0.1 to 99.5, preferably from approximately 0.5 to 95, % by weight of the total mixture.
Apart from the compounds according to the invention, the abovementioned pharmaceutical preparations can also contain further pharmaceutically active compounds.
In general, it is proven advantageous both in human and in veterinary medicine to administer the active compound(s) according to the invention in total amounts of from approximately 0.5 to approximately 500, preferably 5 to 100, mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose contains the active compound(s) according to the invention preferably in amounts of from approximately 1 to approximately 80, in particular 3 to 30, mg/kg of body weight.